The present invention generally relates to improved methods for drug delivery and measurement of analyte using ultrasound in combination with application of an electric field.
Transdermal drug delivery (TDD) offers several advantages over traditional delivery methods including injections and oral delivery. When compared to oral delivery, TDD avoids gastrointestinal drug metabolism, reduces first-pass effects, and provides sustained release of drugs for up to seven days, as reported by Elias, In Percutaneous Absorption: Mechanisms-Methodology-Drag Delivery., Bronaugh, R. L., Maibach, H. 1. (Ed), pp 1-12, Marcel Dekker, New York, 1989. The word "transdermal" is used herein as a generic term. However, in actuality, transport of drugs occurs only across the epidermis where the drug is absorbed in the blood capillaries. When compared to injections, TDD eliminates the associated pain and the possibility of infection. Theoretically, the transdermal route of drug administration could be advantageous in the delivery of many therapeutic proteins, because proteins are susceptible to gastrointestinal degradation and exhibit poor gastrointestinal uptake, proteins such as interferons are cleared rapidly from the blood and need to be delivered at a sustained rate in order to maintain their blood concentration at a high value, and transdermal devices are easier to use than injections.
Ultrasound has been shown to enhance transdermal transport of low-molecular weight drugs (molecular weight less than 500) across human skin, a phenomenon referred to as sonophoresis (Levy, J. Clin Invest. 1989, 83, 2974-2078; Langer, R., In "Topical Drug Bioavailability, Bioequivalence, and Penetration"; pp. 91-103, Shah V. P., M. H. I., Eds. (Plenum: New York, 1993); Frideman, R. M., `Interferons. A Primer`, Academic Press, New York, 1981)). Ultrasound has been shown to create cavitation within the SC, which disorders the lipid bilayers and increases drug transport (Walters, In Transdermal Drug Delivery: Developmental Issues and Research Initiatives, Hadraft, ed. (Marcel Dekker, 1989) pp. 197-233).
U.S. Pat. No. 4,309,989 to Fahim and U.S. Pat. No. 4,767,402 to Kost, et al., disclose various ways in which ultrasound has been used to achieve transdermal drug delivery. Sonophoresis has been shown to enhance transdermal transport of various drugs. Although a variety of ultrasound conditions have been used for sonophoresis, the most commonly used conditions correspond to the therapeutic ultrasound (frequency in the range of 1 MHz-3 MHz, and intensity in the range of 0-2 W/cm.sup.2) (Kost, In Topical Drug Bioavailability Bioequivalence and Penetration, pp. 91-103, Maibach, H. I., Shah, V. P. (Ed) Plenum Press, New York, 1993; U.S. Pat. No. 4,767,402 to Kost, et al.).
In spite of these advantages, very few drugs and no proteins or peptides are currently administered transdermally for clinical applications because of the low skin permeability to drugs. Application of therapeutic ultrasound does not induce transdermal transport of high-molecular weight proteins. It is a common observation that the typical enhancement induced by therapeutic ultrasound is less than ten-fold. In many cases, no enhancement of transdermal drug transport has been observed upon ultrasound application. This low permeability is attributed to the stratum corneum (SC), the outermost skin layer which consists of flat, dead cells filled with keratin fibers (keratinocytes) surrounded by lipid bilayers. The highly-ordered structure of the lipid bilayers confers an impermeable character to the SC (Flynn, G. L., In Percutaneous Absorption: Mechanisms-Methodology-Drug Delivery.; Bronaugh, R. L., Maibach, H. I. (Ed), pages 27-53, Marcel Dekker, New York, 1989).
A variety of approaches have been suggested to enhance transdermal transport of drugs. These include: i) use of chemicals to either modify the skin structure or to increase the drug concentration in the transdermal patch (Junginger, et al. In "Drug Permeation Enhancement"; Hsieh, D.S., Eds., pp. 59-90 (Marcel Dekker, Inc. New York 1994; Burnette, R. R. In Developmental Issues and Research Initiatives; Hadgraft J., G., R. H., Eds., Marcel Dekker: 1989; pp. 247-288); ii) applications of electric fields to create transient transport pathways [electroporation] (Prausnitz Proc. Natl. Acad. Sci. USA 90, 10504-10508 (1993); Walters, K. A., in Transdermal Drug Delivery. Developmental Issues and Research Initiatives, Ed. Hadgraft J., Guy, R. H., Marcel Dekker, 1989) or to increase the mobility of charged drugs through the skin [iontophoresis], and iii) application of ultrasound [sonophoresis]. Various approaches including chemical enhancers [Walters, K. A., in Transdermal Drug Delivery: Developmental Issues and Research Initiatives, Hadgraft J., Guy, R. H., Marcel Dekker: New York (1989)], ultrasound [Levy et al., J. Clin. Invest., 83: 2074-2078 (1989); Mitragotri et al., J. Pharm. Sci, 84:697-706 (1995)] and electrical enhancement [Prausnitz et al. Proc. Natl. Acad. Sci. USA, 90:10504-10508 (1993); Pliquett et al., Pharmaceutical Research, 12:549-555 (1995); Chizmadzhev et al., Biophysical J. 68:749-765 (1995); Burnette (1989)] have been suggested to enhance transdermal drug transport. In some cases, high strengths of the physico-chemical forces (for example, electricity, ultrasound) are required to deliver a given drug dose transdermally. However, the highest strength of these physico-chemical forces that can be used is limited by their adverse physiological effects.
Chemical enhancers have been found to increase transdermal drug transport via several different mechanisms, including increased solubility of the drug in the donor formulation, increased partitioning into the SC, fluidization of the lipid bilayers, and disruption of the intracellular proteins (Kost and Langer, In Topical Drug Bioavailability, Bioequivalence, and Penetration; Shah and Maibech, ed. (Plennum, N.Y. 1993) pp. 91-103 (1993)). U.S. Pat. No. 5,445,611 to Eppstein, et al., describes enhancement of ultrasound using the combination of chemical enhancers with modulation of the frequency, intensity, and/or phase of the ultrasound to induce a type of pumping action. However, the intensity and frequencies used in the examples are quite high, which generates heat and decreasing transport over time.
Electroporation is believed to work in part by creating transient pores in the lipid bilayers of the SC (Burnett (1989)). Iontophoresis provides an electrical driving force to move compounds. Electroporation involves application of electric field pulses that create transient aqueous pathways in lipid bilayer membranes, causing a temporary alteration of skin structure. While occurrence of aqueous pores may allow transdermal permeation of neutral molecules by diffusion, the transport of charged molecules during pulsing occurs predominantly by electrophoresis and electroosmosis.
Accordingly, a better selection of ultrasound parameters is needed to induce a higher enhancement of transdermal drug transport by sonophoresis. Moreover, although efficacy to some degree has been observed using ultrasound for transport of other compounds, the efficiency of transport under conditions acceptable to patients has not been achieved.
It is therefore an object of the present invention to provide a method and means for enhancing transdermal transport.
It is a further object of the present invention to provide methods for using ultrasound in combination with other means of enhancement for drug delivery and collection of analyte in an efficient, practical manner.